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Polyamines are low molecular weight aliphatic polycations, highly charged and ubiquitously present in all living cells. The naturally abundant polyamines are –

1)  Putrescine – H2N–(CH2)4–NH2 (diamine)

 2) Spermidine- H2N–(CH2)4–NH–(CH2)3–NH2 (triamine)

 3) Spermine H2N–(CH2)3–NH–(CH2)4–NH–(CH2)3–NH2 (tetramine)

Significance of Polyamines

The polyamines are involved in a large number of cellular processes. They  exert their role through ionic interactions, owing to their unique structural feature of regularly spaced positive charges. Some of the important functions are as follows-

1) Modulation of chromatin structure

2) Gene transcription and translation

3) DNA stabilization

4) Signal transduction

5) Cell growth and proliferation

6) Membrane stability

7) Functioning of ion channels 

8) Receptor-ligand interactions

9) Pharmacologic doses of polyamines are hypothermic and hypotensive

Since their primary and secondary amino groups are all protonated at physiological pH, putrescine is divalent, spermidine trivalent and spermine tetravalent organic cation. In the cells polyamines interact electrostatically with negatively charged moieties such as DNA, RNA, proteins and phospholipids.The unique feature of polyamine structure compared to inorganic cations like Mg2+ or Ca2+ is that they have positive charges at defined distances and between them methylene groups that can participate in hydrophobic interactions. Thus polyamines form stronger and more specific interactions than inorganic cations.

There is equilibrium between polyamines that are bound to different polyanionic molecules (mainly DNA and RNA) and free polyamines. The free polyamine pool represents 7-10% of the total cellular polyamine content. Only the free intracellular polyamines are available for immediate cellular needs and therefore are subject to strict regulation. Polyamines are maintained within very narrow range because decrease in their concentrations inhibits cell proliferation while excess appears to be toxic.Therefore, the free polyamine pools are regulated in a very fast, sensitive and precise manner.

Synthesis of Polyamines

Polyamine synthesis occurs in the cytoplasm of cells .Polyamines are synthesized from two amino acids: L-Methionine and L-Ornithine (an amino acid that is not incorporated  into tissue proteins, but is an intermediate  of urea cycle).

In mammalian cells, putrescine is formed by decarboxylation of ornithine, a reaction catalyzed by the enzyme ornithine decarboxylase (ODC). Ornithine is available from the plasma and can also be formed within the cell from arginine by the action of arginase. It is possible that arginase, which is much more widely distributed than other enzymes of the urea cycle, is present in extrahepatic tissues to ensure the availability of ornithine for polyamine production. Arginase can, therefore, be thought of as an initial step in polyamine biosynthesis.

For the synthesis of Putrescine , the amino propyl group must be added. This amino propyl moiety is derived from methionine, which is first converted into S-adenosylmethionine and is then decarboxylated. The resulting decarboxylated S-adenosylmethionine is used as an aminopropyl donor in an analogous manner to the use of S-adenosylmethionine itself as a methyl donor. Once it has been decarboxylated, S-adenosylmethionine is committed to Polyamine synthesis. Therefore the concentration of decarboxylated S- adenosylmethionine is kept low and constitutes the rate-limiting factor in spermidine formation. 

Synthesis of spermidine and spermine require the action of two enzymes: first, the S-adenosyl-methionine decarboxylase (AdoMetDC) for the synthesis of decarboxylated S-Adenosyl Methionine, the aminopropyl donor; and second, a transferase enzyme (spermidine synthase or spermine synthase) which catalyze the transfer of the aminopropyl group to the primary amine groups of putrescine or spermidine, respectively (decarboxylated S-Adenosyl Methionine reacts with Putrescine in the presence of Spermidine synthase forming Spermidine and that reacts with another molecule of decarboxylated S-Adenosyl Methionine in the presence of Spemine synthase forming Spermine) (Figure-1)

Ornithine decarboxylase is a B6-P dependent enzyme. It is present in very small amounts in quiescent cells, and its activity can be increased many fold within a few hours of exposure to  hormones, drugs, tissue regeneration, and growth factors. Spermidine  synthase and spermine synthase are discrete enzymes each specific for its own particular substrate.

The other product of the aminopropyl transferase reactions is 5’-methylthioadenosine. Although this nucleoside is produced in stoichiometric amounts with the polyamines, its concentration in the cell is kept low and is rapidly degraded.

Regulation of polyamine biosynthesis

Ornithine decarboxylase and S-Adenosyl decarboxylase are inducible enzymes with short half lives. Hormones like Growth hormone, corticosteroids, testosterone and growth factors increase the activity of Ornithine decarboxylase. Spermidine synthase and spermine synthase are non inducible enzymes.

The activity of S-Adenosyl methionine decarboxylase is inhibited by decarboxylated S-adenosyl Methionine and activated by Putrescine.


An interconversion or recycling pathway converts spermidine and spermine back to putrescine. Spermidine synthase and spermine synthase reactions are effectively irreversible, but it has been known for many years that conversion of spermine into spermidine and spermidine into putrescine can occur in vivo. This interconversion takes place by the action of two enzymes, spermidine-N1-acetyltransferase and polyamine oxidase. The former enzyme uses acetyl CoA to convert spermidine to N1-acetylspermidine and Spermine to N1-acetylspermine. The N1-acetylspermidine or N1-acetylspermine is then oxidized by polyamine oxidase , which cleaves the polyamine at a secondary amino nitrogen to release 3- acetamidopropion aldehyde  and putrescine or spermidine,  depending upon the substrate (Figure-1)

Degradation of Polyamines              

The enzyme polyamine oxidase present in liver peroxisomes oxidizes Spermine to Spermidine, that undergoes oxidation by the same enzyme to form Putrescine. Diamino propane is released, both these are converted to β-amino propane aldehyde. Putrescine is finally oxidized to NH+ and CO2. Major portions of polyamines are excreted in urine as acetylated derivatives (Figure-2)

Clinical Significance

The drug DFMO (Difluoromethyl ornithine) is a powerful inhibitor of polyamine biosynthesis. It inhibits ornithine decarboxylase enzyme and is used for the treatment of African sleeping sickness.


Figure 1. Biosynthesis and interconversion of polyamines. The enzymes catalyzing reactions are: 1.L-methionine S-adenosyltransferase, 2. S-adenosylmethionine decarboxylase , 3. Ornithine decarboxylase , 4. Spermidine synthase , 5. Spermine synthase, 6. Spermidine/spermine N1-acetyltransferase , and 7. Polyamine oxidase.



Figure-2 Showing the degradation of polyamines

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